Additionally, T cell proliferation, which had been slowed by lactic acid, was found to return after treatment with sodium bicarbonate.
In mice transplanted with human AML cells, sodium bicarbonate did not have a toxic effect on the cancer. In fact, the addition of sodium bicarbonate to donor T cells was found to improve survival in mice vs donor T cells alone.
“The data was very convincing in mouse models,” said Sonali Barwe, PhD, of the Nemours Biomedical Research/Alfred I. duPont Hospital for Children in Wilmington, Delaware. “If it works in the preclinical study, the likelihood of working in patients is very high.”
Encouraged by these results, the researchers went on to test sodium bicarbonate in 10 human patients who had relapsed after allo-HCT. Following treatment with sodium bicarbonate over the course of a single week, the patients’ CD8-positive T cells demonstrated improved metabolic fitness and increased respiration.
“Interferon-γ is an indicator that the T cells are in very good health, and that came back after we treated them,” Dr Zeiser said. These promising results warrant a larger clinical trial, which is currently in the planning stages, according to Zeiser.
Further investigation will offer insight on the optimal administration of sodium bicarbonate in this setting. “It remains to be seen how long the treatment needs to be done, what dose needs to be given, and whether it will have sustained impact,” said Dr Barwe. “We saw this effect in patients for a week, but will it be sustained for longer durations? It’s definitely compelling to try.”
Sodium bicarbonate has the advantage of being inexpensive and low toxicity, and could easily be combined with other therapies intended to boost the effectiveness of T cells.
“It will be of great interest to assess the use of sodium bicarbonate as a preventive measure and/or as an intervention upon relapse in well-controlled trials in allo-HCT patients,” Dr Mougiakakos said. “Moreover, sodium bicarbonate could represent a partner of verified low toxicity for other approaches aiming to harness GVL.”
That most functional findings were observed in the mouse models was a limitation of this study. “Determining whether [sodium bicarbonate] improves the GVL effect in humans will require a prospective clinical study,” the investigators said. “Our findings provide a scientific rationale for a combination of donor lymphocyte infusion and sodium bicarbonate in patients relapsing with AML after allo-HCT, in particular when increased lactic acid concentrations are detected as observed in the patients with AML relapse whom we had studied.”
Disclosures: Some of the study authors disclosed financial relationships with the pharmaceutical industry and/or the medical device industry. For a full list of disclosures, please refer to the original study.
Uhl FM, Chen S, O’Sullivan D, et al. Metabolic reprogramming of donor T cells enhances graft-versus-leukemia effects in mice and humans. Sci Transl Med. 2020;12(567):eabb8969. doi:10.1126/scitranslmed.abb8969